Opioid receptor agonists remain the drugs of choice to treat moderate to severe pain, but their use is limited by adverse effects including tolerance, dependence, abuse, and respiratory depression. A recent increase in overdoses and deaths is fueling concerns about opioids that further limit their legitimate medical use. A growing body of evidence indicates that the therapeutic window of an opioid can be increased by combining it with another drug, such that smaller doses of the opioid (in combination with another drug) produce the desired therapeutic effect. Like opioids, cannabinoid receptor agonists have antinociceptive effects and are used to treat pain; however, their use is limited because of adverse effects, including abuse, and because they are effective under a very limited range of conditions when administered alone. Converging lines of evidence indicate that opioid/cannabinoid combinations might be very effective and safe for treating pain. For example, our studies show that in monkeys the potency of opioids to produce antinociception is increased significantly by cannabinoids at doses that do not increase the potency of opioids for producing reinforcing or discriminative stimulus effects. Those results were obtained following acute administration of drugs, although treatment of pain often requires repeated drug treatment. Despite the potential clinical utility of opioid/cannabinoid combinations, little is known about th consequences of repeated daily administration of combinations; the proposed studies extend our initial findings to repeated drug administration to more closely model treatment in pain patients. These studies test the hypothesis that the adverse effects of opioids, that limit their clinical use, are reduced or avoided by combining small doses of an opioid with a cannabinoid. Aim 1 compares the long- term effects of daily dosing with the high efficacy opioid receptor agonist fentanyl administered alone and in combination with the high efficacy cannabinoid receptor agonist CP55,940 to test the hypothesis that administration of an opioid/cannabinoid combination reduces or prevents the development of opioid tolerance and physical dependence. Aim 2 assesses the abuse potential (positive reinforcing effects) of opioid/cannabinoid combinations using a choice procedure in which monkeys choose between fentanyl alone and a combination of fentanyl and CP55,940. Aim 3 characterizes other potential adverse effects of opioid/cannabinoid combinations (sedation, impaired complex task performance, and respiratory depression) and possible pharmacokinetic interactions between fentanyl and CP55,940. These studies will characterize opioid/cannabinoid combinations that increase the therapeutic window of opioids by selectively decreasing the dose of opioid necessary for therapeutic effects, thereby reducing and possibly avoiding the occurrence of adverse effects that currently limit the legitimate medical use of opioids. Using a species and procedures that are highly translatable to humans, these studies will provide proof-of-concept for this innovative approach to pain treatment.